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Objectives: Hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKp) poses a significant threat to public health. This study reports an infection related to hv-CRKp in a premature infant and reveals its colistin resistance and evolutionary mechanisms within the host. Methods: Three KPC-producing CRKp strains were isolated from a patient with sepsis and CRKp osteoarthritis who had been receiving colistin antimicrobial therapy. The minimum inhibitory concentrations (MICs) of ceftazidime, ceftazidime-avibactam (CAZ-AVI), meropenem, imipenem, tigecycline, amikacin, minocycline, sulfamethoxazole/trimethoprim, ciprofloxacin, levofloxacin, aztreonam, cefepime, cefoperazone/sulbactam, piperacillin/tazobactam, and colistin were determined using the microbroth dilution method. The whole-genome sequencing analysis was conducted to determine the sequence types (STs), virulence genes, and antibiotic resistance genes of the three CRKp strains. Results: Whole-genome sequencing revealed that all three CRKp strains belonged to the ST11 clone and carried a plasmid encoding blaKPC-2. The three strains all possessed the iucABCDiutA virulence cluster, peg-344 gene, and rmpA/rmpA2 genes, defining them as hv-CRKp. Further experiments and whole-genome analysis revealed that a strain of K. pneuomniae had developed resistance to colistin. The mechanism found to be responsible for colistin resistance was a deletion mutation of approximately 9000 bp including the mgrB gene. Conclusion: This study characterizes colistin resistance of the ST11 clone hv-CRKp during colistin treatment and its rapid evolution within the host.

Biomaterials play an integral role in treatment of external auditory canal (EAC) diseases. Regarding the special anatomic structure and physiological characteristics of EAC, careful selection of applicable biomaterials was essential step towards effective management of EAC conditions. The bioactive materials can provide reasonable biocompatibility, reduce risk of host pro-inflammatory response and immune rejection, and promote the healing process. In therapeutic procedure, biomaterials were employed for covering or packing the wound, protection of the damaged tissue, and maintaining of normal structures and functions of the EAC. Therefore, understanding and application of biomaterials was key to obtaining great rehabilitation in therapy of EAC diseases. In clinical practice, biomaterials were recognized as an important part in the treatment of different EAC diseases. The choice of biomaterials was distinct according to the requirements of various diseases. As a result, awareness of property regarding different biomaterials was fundamental for appropriate selection of therapeutic substances in different EAC diseases. In this review, we firstly introduced the characteristics of EAC structures and physiology, and EAC pathologies were summarized secondarily. From the viewpoint of biomaterials, the different materials applied to individual diseases were outlined in categories. Besides, the underlying future of therapeutic EAC biomaterials was discussed.

In this investigation, 117718 ionospheric perturbations with a space size t = 20–300 s, but without a limit on amplitude (A), were automatically searched globally via software using ion density data measured by the Detection of Electromagnetic Emissions Transmitted from Earthquake Regions (DEMETER) satellite for approximately six years. After eliminating 18169 perturbations (PERs) that occurred in perturbed time (Kp ≥ 3) in order to avoid the global effects of geomagnetic storms, 99549 PERs were left. These PERs were divided into six groups with respect to local time and season, but only the summer and winter PERs were kept for good comparison. Each group of PERs was distributed on a map in terms of amplitude and space size. The distributions of all groups of plasma PERs showed that the equatorial ionization anomaly (EIA) structure developed well during the winter daytime. This structure is characterized by a low plasma PER density (Np) on both sides of the magnetic equator at low latitudes and a sudden enhancement of Np at a magnetic latitude of 15° at both sides of the magnetic latitudes. At the same time, this daytime anomaly was also clearly presented with a simultaneous enhancement in both Np and space size, even beyond 200 s along its boundary line. From the viewpoint of space size, there is a demarcation point, t = 120 s; the occurrence probabilities of day PERs are always higher than those at night before this point, whereas this result is reversed after this point. Another key point is that large spatial-scale perturbations (t > 200 s) present their major significance during daytime, especially during summer daytime, probably due to ionization under strong sunlight. The WSA (Wedell Sea Anomaly) phenomenon shows a clear configuration at all times except on the summer day. The topside ionosphere remained calm during the day in summer, and no positive PERs with a magnitude of more than 50% or a negative magnitude of more than 100% occurred in this WSA area. In winter nighttime, this WSA structure was characterized by major large positive PERs with a magnitude of more than 100%.

Abstract Background The prognostic value of circulating tumor cells (CTCs) in metastatic breast cancer (MBC) has been extensively studied and verified by the CellSearch® system. Varieties of microfluidic systems have been developed to improve capture efficiency with the lack of standardization and automation. This study systematically verified the positive threshold for prognosis and its guidance value in anti-HER2 therapy based on a novel automated microfluidic system OmiCell®. Methods CTCs isolation, enumeration and labeling were performed using the OmiCell® system. CTCs identification and reporting were performed using the DeepSight® scanning system. Results The capture efficiency and specificity of OmiCell® system was 91.9% and 90%, respectively. Then, 65 MBC patients with known HER2 status of their metastatic tumors were enrolled. In the cohort, we detected ≥ 1 CTCs in 59 patients (90.8%, range: 1–55 CTCs, median = 6),

Abstract Photosystem II (PSII) catalyzes the light-driven charge separation and water oxidation reactions of photosynthesis. Eukaryotic PSII core is usually associated with membrane-embedded light-harvesting antennae, which greatly increase the absorbance cross-section of the core. The peripheral antennae in different phototrophs vary considerably in protein composition and arrangement. Photosynthetic cryptophytes possess chlorophyll a/c binding proteins (CACs) that serve as their antennae. How these CACs assemble with the PSII core remains unclear. Here, we report the 2.57-Å resolution structure of cryptophyte PSII-CAC purified from cells at nitrogen-limited stationary growth phase. We show that each monomer of the PSII homodimer contains a core complex, six chlorophyll a/c binding proteins (CACs) and a previously unseen chlorophyll-binding protein (termed CAL-II). Six CACs are arranged as a double-layered arc-shaped non-parallel belt, and two such belts attach to the dimeric core from opposite sides. The CAL-II simultaneously interacts with a number of core subunits and five CACs. The distinct organization of CACs and the presence of CAL-II may play a critical role in stabilizing the dimeric PSII-CAC complex under stress conditions. Our study provides mechanistic insights into the assembly and function of the PSII-CAC complex as well as the possible adaptation of cryptophytes in response to environmental stresses.

Abstract Mogrosides constitute a series of natural sweeteners extracted from Siraitia grosvenorii fruits. These mogrosides are glucosylated to different degrees, with mogroside V (M5) and siamenoside I (SIA) being two mogrosides with high intensities of sweetness. SgUGT94-289-3 constitutes a uridine diphosphate (UDP)-dependent glycosyltransferase (UGT) responsible for the biosynthesis of M5 and SIA, by continuously catalyzing glucosylation on mogroside IIe (M2E) and on the subsequent intermediate mogroside products. However, the mechanism of its promiscuous substrate recognition and multiple catalytic modes remains unclear. Here, we report multiple complex structures and the enzymatic characterization of the glycosyltransferase SgUGT94-289-3. We show that SgUGT94-289-3 adopts a dual-pocket organization in its active site, which allows the two structurally distinct reactive ends of mogrosides to be presented from different pockets to the active site for glucosylation reaction, thus enabling both substrate promiscuity and catalytic regioselectivity. We further identified a structural motif that is essential to catalytic activity and regioselectivity, and generated SgUGT94-289-3 mutants with greatly improved M5/SIA production from M2E in an in vitro one-pot setup.

Abstract Triple negative breast cancer (TNBC) has the characteristics of low immune cell infiltration, high expression of tumor programmed death ligand 1 (PD-L1), and abundant cancer stem cells. Systemic toxicity of traditional chemotherapy drugs due to poor drug selectivity, and chemotherapy failure due to tumor drug resistance and other problems, so it is particularly important to find new cancer treatment strategies for TNBC with limited treatment options. Both the anti-tumor natural drugs curcumin and ginsenoside Rg3 can exert anti-tumor effects by inducing immunogenic cell death (ICD) of tumor cells, reducing PD-L1 expression, and reducing cancer stem cells. However, they have the disadvantages of poor water solubility, low bioavailability, and weak anti-tumor effect of single agents. We used vinyl ether bonds to link curcumin (Cur) with N-O type zwitterionic polymers and at the same time encapsulated ginsenoside Rg3 to obtain hyperbranched zwitterionic drug-loaded micelles OPDEA-PGED-5HA@Cur@Rg3 (PPH@CR) with pH response. In vitro cell experiments and in vivo animal experiments have proved that PPH@CR could not only promote the maturation of dendritic cells (DCs) and increase the CD4+ T cells and CD8+ T cells by inducing ICD in tumor cells but also reduce the expression of PD-L1 in tumor tissues, and reduce cancer stem cells and showed better anti-tumor effects and good biological safety compared with free double drugs, which is a promising cancer treatment strategy.

Accurately extracting surface deformation is essential for the prevention and control of geological hazards caused by underground coal mining. By taking a working face in Guotun Coal Mine, Shandong Province, as the case study, this paper first obtains 18 Sentinel-1A satellite images during the extraction period of the working face (July 31, 2017, to May 3, 2018), and derives the surface deformation of the goaf area based on SBAS-InSAR technology. Then, driven by InSAR observations, the functional projection relationships for the three-dimensional parameters between the probability integration method (PIM) and line-of-sight (LOS) deformation derived by SBAS-InSAR are deduced, and a three-dimensional and full-parameter inversion model based on genetic algorithm with random error elimination (GAREE) is proposed. Based on this model, the subsidence parameters inside the study area are accurately retrieved with the deviation for each parameter less than 3% compared with the empirical parameters. Finally, by using the retrieved parameters, PIM is employed to predict the whole goad deformation with the predicted results highly consistent with the field leveling data. The root mean square errors (RMSE) on observation line A and line F are 0.083 m and 0.102 m, respectively, and the mean absolute errors (MAE) are 0.068 m and 0.089 m, respectively. Results show that the parameter inversion model proposed by this study can effectively obtain the subsidence information for the whole basin of a mining goaf in a low-cost way, providing scientific and significant importance for engineering application and potential disaster predictions in coal mining areas.

Objective·To construct and verify the mouse model that can mimic the vitamin A deficiency (VAD)-like craniofacial skeletal deformity and do not cause embryonic death.Methods·Based on the Cre-LoxP system, the OsxCre;Rosa26dn/dn mice expressing osteoblast-specific dominant-negative retinoid acid receptor α (dnRARα) mutation were obtained by hybridization through OsxCre and Rosa26dnRARα/dnRARα mice, to achieve the conditional inhibition of retinoic acid signaling to simulate VAD disease. Femur bone mesenchymal stem cells (BMSCs) and parietal bone cells of OsxCre;Rosa26dn/dn mice and their control littermates were isolated and underwent osteogenic induction, to assess the expression of retinoid acid receptor α (RARα) protein through Western blotting. Osteoblasts induced from parietal bone cells of OsxCre;Rosa26dn/dn mice and their control littermates were isolated and the effect of retinoic acid signaling inhibition was verified through dual luciferase gene reporter assay. Meanwhile, Ad-eGFP or Ad-Cre adenovirus-infected femur BMSCs and parietal bone cells of Rosa26dn/dn mice underwent osteogenic induction to assess the expression of dominant-negative mutant protein and the inhibition of the retinoic acid signaling pathway in vitro by Western blotting and dual luciferase gene reporter assay. Moreover, the skulls of 6-week-old OsxCre;Rosa26dn/dn mice were collected, and Micro-CT scanning and three-dimensional (3D) reconstruction were performed to verify the craniofacial skeletal deformities of the mouse model.Results·Western blotting results demonstrated that the level of RARα protein increased in the femur and parietal osteoblasts of OsxCre;Rosa26dn/dn mice compared to that of their control littermates, and also increased in the Ad-Cre-infected femur and parietal osteoblasts of Rosa26dn/dn mice compared to that in the Ad-eGFP-infected group (P

Abstract Background Ovarian clear cell carcinoma (OCCC), well known for its chemoresistance to platinum-based chemotherapy, exhibited a good response in clinical trials of anti–PD-1/PD-L1 inhibitors. By assessing PD-L1 expression, we sought to determine the potential therapeutic benefit of PD-1/PD-L1 inhibitors in OCCC. Methods and results The retrospective study included 152 individuals with OCCC between 2019 and 2022 at Peking Union Medical College Hospital. Paired tumors of primary versus recurrent lesions (17 pairs from 15 patients) or primary versus metastatic lesions (11 pairs from 9 patients) were also included. The 22C3 pharmDx assay and whole sections were used for PD-L1 immunohistochemical staining. Pathologists with experience in premarket clinical trials evaluated PD-L1 expression based on various diagnostic criteria (TPS 1%, CPS 1, or CPS 10). The number and percentage of positive PD-L1 cases were 34 (22.4%, TPS ≥ 1%) and 59 (38.8%, CPS ≥ 1), respectively. Thirty-three (21.7%) of the cases had high PD-L1 expression (CPS ≥ 10). Half of the platinum-resistant patients (11/22) were PD-L1 positive (CPS ≥ 1). In addition, positive PD-L1 expression (CPS ≥ 1) was related to clinicopathological characteristics that represented a worse prognosis, such as advanced stages, lymph node metastasis, and distant metastasis (p = 0.032, p

Abstract Background Cesarean section-induced postpartum hemorrhage (PPH) potentially causes anemia and hypovolemic shock in pregnant women. Hence, it is helpful for obstetricians and anesthesiologists to prepare pre-emptive prevention when predicting PPH occurrence in advance. However, current works on PPH prediction focus on whether PPH occurs rather than assessing PPH amount. To this end, this work studies quantitative PPH prediction with machine learning (ML). Methods The study cohort in this paper was selected from individuals with PPH who were hospitalized at Shijiazhuang Obstetrics and Gynecology Hospital from 2020 to 2022. In this study cohort, we built a dataset with 6,144 subjects covering clinical parameters, anesthesia operation records, laboratory examination results, and other information in the electronic medical record system. Based on our built dataset, we exploit six different ML models, including logistic regression, linear regression, gradient boosting, XGBoost, multilayer perceptron, and random forest, to automatically predict the amount of bleeding during cesarean section. Eighty percent of the dataset was used as model training, and 20 $$\%$$ % was used for verification. Those ML models are constantly verified and improved by root mean squared error(RMSE) and mean absolute error(MAE). Moreover, we also leverage the importance of permutation and partial dependence plot (PDP) to discuss their feasibility. Result The experiment results show that random forest obtains the highest accuracy for PPH amount prediction compared to other ML methods. Random forest reaches the mean absolute error of 21.7, less than 5.4 $$\%$$ % prediction error. It also gains the root mean squared error of 33.75, less than 9.3 $$\%$$ % prediction error. On the other hand, the experimental results also disclose indicators that contributed most to PPH prediction, including Ca, hemoglobin, white blood cells, platelets, Na, and K. Conclusion It effectively predicts the amount of PPH during a cesarean section by ML methods, especially random forest. With the above insight, ML predicting PPH amounts provides early warning for clinicians, thus reducing complications and improving cesarean sections’ safety. Furthermore, the importance of ML and permutation, complemented by incorporating PDP, promises to provide clinicians with a transparent indication of individual risk prediction.

Abstract Studies on Bdellovibrio and like organisms (BALOs), obligate predatory bacteria, have highlighted the possibility of regulating bacteria and biofilms; however, yak-derived BALOs are yet to be reported. We aimed to characterize the BALOs isolated and identified from yak (Bos grunniens) feces and examine application potential. BALOs were isolated from healthy yak fecal samples, with Escherichia coli (ATCC 25922) as prey using the double-layer agar method, identified by transmission electron microscopy (TEM), and the specific 16S rDNA sequencing analysis. Sequencing of the 16S rDNA gene indicated that this isolate was 91% similar to the Bdellovibrio sp. NC01 reference strain and was named YBD-1. Proportion of YBD-1 lysed bacteria is 12/13. The YBD-1 showed best growth at 25–40°C, 0–0.25% (w/v) NaCl, and pH 6.5–7.5. YBD-1 significantly reduced the planktonic cells and biofilms of E.coli in co-culture compared to the E.coli group. Additionally, SEM analysis indicated that YBD-1 significantly reduced biofilm formation in E. coli. Furthermore, quantitative Real Time-polymerase chain reaction (qRT-PCR) showed that the expression of the virulence genes fim and iroN and the genes pgaABC involved in biofilm formation went down significantly. We concluded that YBD-1 may have the potential to control bacterial growth and biofilm-associated bacterial illnesses.

Abstract Immunodeficient murine models are usually used as the preclinical models of osteosarcoma. Such models do not effectively simulate the process of tumorigenesis and metastasis. Establishing a suitable animal model for understanding the mechanism of osteosarcoma and the clinical translation is indispensable. The UMR-106 cell suspension was injected into the marrow cavity of Balb/C nude mice. Tumor masses were harvested from nude mice and sectioned. The tumor fragments were transplanted into the marrow cavities of SD rats immunosuppressed with cyclosporine A. Through muti-rounds selection in SD rats, we constructed orthotopic osteosarcoma animal models using rats with intact immune systems. The primary tumor cells were cultured in-vitro to obtain the immune-tolerant cell line. VX2 tumor fragments were transplanted into the distal femur and parosteal radius of New Zealand white rabbit to construct orthotopic osteosarcoma animal models in rabbits. The rate of tumor formation in SD rats (P1 generation) was 30%. After four rounds of selection and six rounds of acclimatization in SD rats with intact immune systems, we obtained immune-tolerant cell lines and established the orthotopic osteosarcoma model of the distal femur in SD rats. Micro-CT images confirmed tumor-driven osteolysis and the bone destruction process. Moreover, the orthotopic model was also established in New Zealand white rabbits by implanting VX2 tumor fragments into rabbit radii and femurs. We constructed orthotopic osteosarcoma animal models in rats with intact immune systems through muti-rounds in-vivo selection and the rabbit osteosarcoma model.

The reachable set estimation for two-dimensional (2-D) switched nonlinear positive systems (SNPSs) with bounded disturbances given by the Roesser model is investigated in this paper, in which both the time-varying delays and lagged impulsive effects are taken into account. By applying the average dwell time (ADT) technique, we provide a sufficient condition for the presence of a ball such that any solution of the system converges exponentially within it. An accurate estimate of the convergence rate is provided. We also extend the result to 2-D SNPSs with multi-directional delays, general 2-D switched linear systems, and 2-D SPNSs with heterogeneous delays. Finally, an example is worked out to demonstrate the effectiveness of the main result.

Abstract Biostimulants are heterogeneous products designed to support plant development and to improve the yield and quality of crops. Here, we focused on the effects of triacontanol, a promising biostimulant found in cuticle waxes, on tomato growth and productivity. We examined various phenological traits related to vegetative growth, flowering and fruit yield, the metabolic profile of fruits, and the response of triacontanol-treated plants to salt stress. Additionally, a proteomic analysis was conducted to clarify the molecular mechanisms underlying triacontanol action. Triacontanol application induced advanced and increased blooming without affecting plant growth. Biochemical analyses of fruits showed minimal changes in nutritional properties. The treatment also increased the germination rate of seeds by altering hormone homeostasis and reduced salt stress-induced damage. Proteomics analysis of leaves revealed that triacontanol increased the abundance of proteins related to development and abiotic stress, while down-regulating proteins involved in biotic stress resistance. The proteome of the fruits was not significantly affected by triacontanol, confirming that biostimulation did not alter the nutritional properties of fruits. Overall, our findings provide evidence of the effects of triacontanol on growth, development, and stress tolerance, shedding light on its mechanism of action and providing new insights into its potential in agricultural practices.

Abstract Influenza viruses and thogotoviruses account for most recognized orthomyxoviruses. Thogotoviruses, exemplified by Thogoto virus (THOV), are capable of infecting humans using ticks as vectors. THOV transcribes mRNA without the extraneous 5′ end sequences derived from cap-snatching in influenza virus mRNA. Here, we report cryo-EM structures to characterize THOV polymerase RNA synthesis initiation and elongation. The structures demonstrate that THOV RNA transcription and replication are able to start with short dinucleotide primers and that the polymerase cap-snatching machinery is likely non-functional. Triggered by RNA synthesis, asymmetric THOV polymerase dimers can form without the involvement of host factors. We confirm that, distinctive from influenza viruses, THOV-polymerase RNA synthesis is weakly dependent of the host factors ANP32A/B/E in human cells. This study demonstrates varied mechanisms in RNA synthesis and host factor utilization among orthomyxoviruses, providing insights into the mechanisms behind thogotoviruses’ broad-infectivity range.

Abstract Podocytes are specialized terminally differentiated cells in the glomerulus that are the primary target cells in many glomerular diseases. However, the current podocyte cell lines suffer from prolonged in vitro differentiation and limited survival time, which impede research progress. Therefore, it is necessary to establish a cell line that exhibits superior performance and characteristics. We propose a simple protocol to obtain an immortalized mouse podocyte cell (MPC) line from suckling mouse kidneys. Primary podocytes were cultured in vitro and infected with the SV40 tsA58 gene to obtain immortalized MPCs. The podocytes were characterized using Western blotting and quantitative real-time PCR. Podocyte injury was examined using the Cell Counting Kit-8 assay and flow cytometry. First, we successfully isolated an MPC line and identified 39 °C as the optimal differentiation temperature. Compared to undifferentiated MPCs, the expression of WT1 and synaptopodin was upregulated in differentiated MPCs. Second, the MPCs ceased proliferating at a nonpermissive temperature after day 4, and podocyte-specific proteins were expressed normally after at least 15 passages. Finally, podocyte injury models were induced to simulate podocyte injury in vitro. In summary, we provide a simple and popularized protocol to establish a conditionally immortalized MPC, which is a powerful tool for the study of podocytes.

Abstract Background Aldosterone plays important parts in development of cardio-metabolic diseases as end product of renin-angiotensin-aldosterone system. However, factors elevating circulating aldosterone are not clear, and lifestyle-related factors are suggested to be involved, whereas less studied. Therefore, we aimed to explore the association of lifestyle factors with plasma aldosterone concentration (PAC) in community population. Methods In this cross-sectional study, we recruited participants using multistage random sampling from Emin China in 2019, and collected data and fasting blood samples. The considered lifestyle factors included obesity parameters (neck circumference, abdominal circumference), alcohol consumption, blood pressure (BP), physical activity, sleep duration, sleep quality, mental state (depression and anxiety), fasting blood glucose (FBG), and lipid profiles (total cholesterol and triglyceride). PAC was measured using radioimmunoassay. We performed sex-stratified linear and logistic regressions to explore associated factors of PAC. Component analysis was further performed to identify the main factors affecting PAC. Results Twenty-seven thousand four hundred thirty-six participants with 47.1% men were included. Obesity parameters (neck circumference, abdominal circumference), glucose metabolism (FBG), psychological status (anxiety status in men and women, depression status in men), BP, liver function (in men), lipid metabolism (TC and TG in men), sleep parameters (sleep quality in women), and renal function (in women) are the main factors associated with elevated PAC. Conclusion lower physical activity, alcohol consumption, higher BP, fat accumulation, dyslipidemia, higher fasting blood glucose, and presence of depression and anxiety were the main factors associated with eleveated PAC.

Abstract Objectives At present, there are many limitations in the evaluation of lymph node metastasis of lung adenocarcinoma. Currently, there is a demand for a safe and accurate method to predict lymph node metastasis of lung cancer. In this study, radiomics was used to accurately predict the lymph node status of lung adenocarcinoma patients based on contrast-enhanced CT. Methods A total of 503 cases that fulfilled the analysis requirements were gathered from two distinct hospitals. Among these, 287 patients exhibited lymph node metastasis (LNM +) while 216 patients were confirmed to be without lymph node metastasis (LNM-). Using both traditional and deep learning methods, 22,318 features were extracted from the segmented images of each patient's enhanced CT. Then, the spearman test and the least absolute shrinkage and selection operator were used to effectively reduce the dimension of the feature data, enabling us to focus on the most pertinent features and enhance the overall analysis. Finally, the classification model of lung adenocarcinoma lymph node metastasis was constructed by machine learning algorithm. The Accuracy, AUC, Specificity, Precision, Recall and F1 were used to evaluate the efficiency of the model. Results By incorporating a comprehensively selected set of features, the extreme gradient boosting method (XGBoost) effectively distinguished the status of lymph nodes in patients with lung adenocarcinoma. The Accuracy, AUC, Specificity, Precision, Recall and F1 of the prediction model performance on the external test set were 0.765, 0.845, 0.705, 0.784, 0.811 and 0.797, respectively. Moreover, the decision curve analysis, calibration curve and confusion matrix of the model on the external test set all indicated the stability and accuracy of the model. Conclusions Leveraging enhanced CT images, our study introduces a noninvasive classification prediction model based on the extreme gradient boosting method. This approach exhibits remarkable precision in identifying the lymph node status of lung adenocarcinoma patients, offering a safe and accurate alternative to invasive procedures. By providing clinicians with a reliable tool for diagnosing and assessing disease progression, our method holds the potential to significantly improve patient outcomes and enhance the overall quality of clinical practice.

Abstract Oxidative stress is increasingly recognized as a major contributor to the pathophysiology of Alzheimer’s disease (AD), particularly in the early stages of the disease. The multiplicity advantages of stem cell transplantation make it fascinating therapeutic strategy for many neurodegenerative diseases. We herein demonstrated that human dental pulp stem cells (hDPSCs) mediated oxidative stress improvement and neuroreparative effects in in vitro AD models, playing critical roles in regulating the polarization of hyperreactive microglia cells and the recovery of damaged neurons. Importantly, these therapeutic effects were reflected in 10-month-old 3xTg-AD mice after a single transplantation of hDPSCs, with the treated mice showing significant improvement in cognitive function and neuropathological features. Mechanistically, antioxidant and neuroprotective effects, as well as cognitive enhancements elicited by hDPSCs, were at least partially mediated by Nrf2 nuclear accumulation and downstream antioxidant enzymes expression through the activation of the AKT-GSK3β-Nrf2 signaling pathway. In conclusion, our findings corroborated the neuroprotective capacity of hDPSCs to reshape the neuropathological microenvironment in both in vitro and in vivo AD models, which may be a tremendous potential therapeutic candidate for Alzheimer’s disease.

Abstract Objective Cerebral malperfusion (CM) is a common comorbidity in acute type A aortic dissection (ATAAD), which is associated with high mortality and poor neurological prognosis. This meta-analysis investigated the surgical strategy of ATAAD patients with CM, aiming to compare the difference in therapeutic effectiveness between the central repair-first and the early reperfusion-first according to clinical outcomes. Methods The meta-analysis and systematic review was conducted based on studies sourced from the PubMed, Embase, and Cochrane literature database, in which cases of ATAAD with CM underwent surgical repair were included. Data for baseline characteristics, mortality, survival were extracted, and risk ratio (RR) values and the pooled mortality were calculated. Results A total of 17 retrospective studies were analyzed, including 1010 cases of ATAAD with CM underwent surgical repair. The pooled early mortality in early reperfusion group was lower (8.1%; CI, 0.02 to 0.168) than that in the central repair group (16.2%; CI, 0.115 to 0.216). The pooled long-term mortality was 7.9% in the early reperfusion cohort and 17.4% the central repair-first cohort, without a statistically significant heterogeneity (I [2] = 51.271%; p = 0.056). The mean time of symptom-onset-to-the-operation-room in all the reports was 8.87 ± 12.3 h. Conclusion This meta-analysis suggested that early reperfusion-first may achieved better outcomes compared to central repair-first in ATAAD patients complicated with CM to some extent. Early operation and early restoration of cerebral perfusion may reduce the occurrence of some neurological complications. Trial registration : The meta-analysis was registered in the International Prospective Register of Systematic Reviews database (No. CRD CRD42023475629) on Nov. 8th, 2023.

Abstract Cd contamination, especially in farmland soil, can pose serious threats to human health as well as ecological security. Stabilization is an important strategy for agricultural soil Cd remediation. In this study, a Cd-resistant strain (Cupriavidus B-7) was isolated and loaded onto cow manure (CDB), rice straw (RSB) and pine wood biochar (PB) to investigate its effects on Cd stabilization by a 60-day pot experiment. Results indicated that the Cupriavidus B-7-loaded biochar (labelled as CDBB, PBB and RSBB) reduced the CaCl2-extractable Cd by 43.06–59.78%, which was significantly superior to individual applications of Cupriavidus B-7 and biochar. Likewise, the soil physicochemical properties, urease, catalase and phosphatase activities were improved, indicating improved soil health. Consequently, dry weights of pakchoi’s shoot and root were increased by 938.9–1230.9% and 149.1–281.2%, respectively, by applying CDBB, PBB and RSBB. Meanwhile, the Cd accumulation in pakchoi shoots decreased by 38.06–50.75%. Notably, the RSBB exhibited an optimal performance on pakchoi growth promotion and Cd accumulation alleviation. The structural equation model indicated the synergistic effect on pakchoi growth promotion and Cd accumulation decreased between biochar and Cupriavidus B-7. Our research provides some new insights into the development of strategies for green and sustainable remediation of Cd-contaminated soil. Graphical Abstract

Abstract Photosynthetic cryptophytes are eukaryotic algae that utilize membrane-embedded chlorophyll a/c binding proteins (CACs) and lumen-localized phycobiliproteins (PBPs) as their light-harvesting antennae. Cryptophytes go through logarithmic and stationary growth phases, and may adjust their light-harvesting capability according to their particular growth state. How cryptophytes change the type/arrangement of the photosynthetic antenna proteins to regulate their light-harvesting remains unknown. Here we solve four structures of cryptophyte photosystem I (PSI) bound with CACs that show the rearrangement of CACs at different growth phases. We identify a cryptophyte-unique protein, PsaQ, which harbors two chlorophyll molecules. PsaQ specifically binds to the lumenal region of PSI during logarithmic growth phase and may assist the association of PBPs with photosystems and energy transfer from PBPs to photosystems.

Due to the excellent biocompatibility of Zn, Ag, and Ca, these elements were chosen for the development of a Mg–Zn–Ag–Ca alloy system for biomedical applications. This study studied the effect of Ca on the microstructure and corrosion behavior of as-cast Mg–Zn-0.5Ag-xCa alloy. The composition and microstructure of the alloys were analyzed using metallographic microscopy, scanning electron microscopy, transmission electron microscopy, and X-ray diffractometry. The alloys were immersed in Hank's solution for weight loss experiments to analyze the corrosion rate and micro-corrosion morphology of alloys with different Ca contents. It was observed that with the increase of Ca content, grain refinement and the amount of the second phase increased. Corrosion tests in Hank's solution demonstrated that a minor addition of Ca could reduce the corrosion rate, but the rate increased sharply once the Ca content exceeded 1.0 wt%. Considering corrosion performance, the optimal range of Ca concentration was determined to be 1.0 wt% to 1.5 wt%.

Mirostrellus joffrei Thomas, 1915 is the sole species within the genus Mirostrellus and its occurrence is notably rare in China. Despite the recent discovery of four previously unreported specimens from western Yunnan, China (Zaoteng River, 25.31°N, 98.80°E, altitude 1451 m) at the National Museum of Prague in the Czech Republic, comprehensive descriptions or detailed accounts of this species within China have yet to be published.During a field expedition within the Guanyinshan Provincial Nature Reserve, Yuanyang, Yunnan, China, a bat was captured using a mist net. The specimen was of moderate size, with its ventral surface presenting a golden-brown hue and its dorsal surface ranging from dark brown to obsidian. The forearm measured 37.31 mm, while the fifth digit was conspicuously diminished in comparison to the others. The snout was robust, featuring prominent buccal glands. It was characterised by a well-developed upper frame and a barely visible low sagittal crest. The upper canines possessed well-developed posterior cusps. The dentition comprised two upper and two lower premolars, with the first upper premolar being notably small and the lower molars being distinctly myotodont. These attributes correspond with the known traits of Mirostrellus joffrei. Phylogenetically, the sequence of this specimen clustered with that of M. joffrei, forming an independent clade. Through an examination of its morphological characteristics and a phylogenetic analysis of the mitochondrial cytochrome b (Cyt b), cytochrome oxidase subunit I (COI) and recombination activating gene 2 (RAG2) sequences, we identified the specimen as M. joffrei, thus confirming the presence of Joffre’s pipistrelle in China.

Abstract Background Brassica napus, a hybrid resulting from the crossing of Brassica rapa and Brassica oleracea, is one of the most important oil crops. Despite its significance, B. napus productivity faces substantial challenges due to heavy metal stress, especially in response to cadmium (Cd), which poses a significant threat among heavy metals. Natural resistance-associated macrophage proteins (NRAMPs) play pivotal roles in Cd uptake and transport within plants. However, our understanding of the role of BnNRAMPs in B. napus is limited. Thus, this study aimed to conduct genome-wide identification and bioinformatics analysis of three Brassica species: B. napus, B. rapa, and B. oleracea. Results A total of 37 NRAMPs were identified across the three Brassica species and classified into two distinct subfamilies based on evolutionary relationships. Conservative motif analysis revealed that motif 6 and motif 8 might significantly contribute to the differentiation between subfamily I and subfamily II within Brassica species. Evolutionary analyses and chromosome mapping revealed a reduction in the NRAMP gene family during B. napus evolutionary history, resulting in the loss of an orthologous gene derived from BoNRAMP3.2. Cis-acting element analysis suggested potential regulation of the NRAMP gene family by specific plant hormones, such as abscisic acid (ABA) and methyl jasmonate (MeJA). However, gene expression pattern analyses under hormonal or stress treatments indicated limited responsiveness of the NRAMP gene family to these treatments, warranting further experimental validation. Under Cd stress in B. napus, expression pattern analysis of the NRAMP gene family revealed a decrease in the expression levels of most BnNRAMP genes with increasing Cd concentrations. Notably, BnNRAMP5.1/5.2 exhibited a unique response pattern, being stimulated at low Cd concentrations and inhibited at high Cd concentrations, suggesting potential response mechanisms distinct from those of other NRAMP genes. Conclusions In summary, this study indicates complex molecular dynamics within the NRAMP gene family under Cd stress, suggesting potential applications in enhancing plant resilience, particularly against Cd. The findings also offer valuable insights for further understanding the functionality and regulatory mechanisms of the NRAMP gene family.

Abstract Background Cystic fibrosis is a chronic genetic disease that can affect the function of the respiratory system. Previous reviews of the effects of respiratory muscle training in people with cystic fibrosis are uncertain and do not consider the effect of age on disease progression. This systematic review aims to determine the effectiveness of respiratory muscle training in the clinical outcomes of children and adolescents with cystic fibrosis. Methods Up to July 2023, electronic databases and clinical trial registries were searched. Controlled clinical trials comparing respiratory muscle training with sham intervention or no intervention in children and adolescents with cystic fibrosis. The primary outcomes were respiratory muscle strength, respiratory muscle endurance, lung function, and cough. Secondary outcomes included exercise capacity, quality of life and adverse events. Two review authors independently extracted data and assessed study quality using the Cochrane Risk of Bias Tool 2. The certainty of the evidence was assessed according to the GRADE approach. Meta-analyses where possible; otherwise, take a qualitative approach. Results Six studies with a total of 151 participants met the inclusion criteria for this review. Two of the six included studies were published in abstract form only, limiting the available information. Four studies were parallel studies and two were cross-over designs. There were significant differences in the methods and quality of the methodology included in the studies. The pooled data showed no difference in respiratory muscle strength, lung function, and exercise capacity between the treatment and control groups. However, subgroup analyses suggest that inspiratory muscle training is beneficial in increasing maximal inspiratory pressure, and qualitative analyses suggest that respiratory muscle training may benefit respiratory muscle endurance without any adverse effects. Conclusions This systematic review and meta-analysis indicate that although the level of evidence indicating the benefits of respiratory muscle training is low, its clinical significance suggests that we further study the methodological quality to determine the effectiveness of training. Trial registration The protocol for this review was recorded in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42023441829.

SUMMARY: The administration of drugs via the oral route is challenging due to the presence of physiologic barrier. BCRP, which can actively transport substrates from intra- to extracellular environment, has an important functional role in the composition of physiologic barrier. Therefore, overcoming BCRP efflux is a strategy to improve the absorption of substrate drugs. Curcumin is a natural feed additive for poultry health and production. However, it is unknown whether curcumin affects the expression of BCRP. The purpose of this study was to investigate the role of curcumin in the regulation of BCRP and its influences on pharmacokinetics of BCRP substrate florfenicol. Results showed that curcumin (60 μM) inhibited the expression of BCRP mRNA by 58% and BCRP protein by 52% in primary chicken hepatocytes. Moreover, intracellular mitoxantrone (a selective BCRP substrate) fluorescence was 1.58-fold higher in cells pretreated with 60 μM curcumin than in untreated cells, indicating that curcumin inhibited the transport function of BCRP. In vivo experiments showed that curcumin reduced BCRP expression in the liver, kidney, duodenum, jejunum and ileum of chicken. Coadministration of curcumin (150 mg/kg) significantly changed the pharmacokinetic behavior of orally administered florfenicol (substrate of chicken BCRP), with a higher area under the curve (35.51 vs. 25.81 h·ug/L) and a higher Cmax values (9.94 vs. 7.61 μg/mL). The bioavailability of orally administered florfenicol was increased from 51.6 to 72.8% by curcumin. Together, our results indicate that curcumin inhibited the expression and efflux function of BCRP in chicken and improved the bioavailability of BCRP substrate florfenicol.

Articular cartilage defect therapy is still dissatisfactory in clinic. Direct cell implantation faces challenges, such as tumorigenicity, immunogenicity, and uncontrollability. Extracellular vesicles (EVs) based cell-free therapy becomes a promising alternative approach for cartilage regeneration. Even though, EVs from different cells exhibit heterogeneous characteristics and effects. The aim of the study was to discover the functions of EVs from the cells during chondrogenesis timeline on cartilage regeneration. Here, bone marrow mesenchymal stem cells (BMSCs)-EVs, juvenile chondrocytes-EVs, and adult chondrocytes-EVs were used to represent the EVs at different differentiation stages, and fibroblast-EVs as surrounding signals were also joined to compare. Fibroblasts-EVs showed the worst effect on chondrogenesis. While juvenile chondrocyte-EVs and adult chondrocyte-EVs showed comparable effect on chondrogenic differentiation as BMSCs-EVs, BMSCs-EVs showed the best effect on cell proliferation and migration. Moreover, the amount of EVs secreted from BMSCs were much more than that from chondrocytes. An injectable decellularized extracellular matrix (dECM) hydrogel from small intestinal submucosa (SIS) was fabricated as the EVs delivery platform with natural matrix microenvironment. In a rat model, BMSCs-EVs loaded SIS hydrogel was injected into the articular cartilage defects and significantly enhanced cartilage regeneration in vivo. Furthermore, protein proteomics revealed BMSCs-EVs specifically upregulated multiple metabolic and biosynthetic processes, which might be the potential mechanism. Thus, injectable SIS hydrogel loaded with BMSCs-EVs might be a promising therapeutic way for articular cartilage defect.

Crayfish (Procambarus clarkii) are economically important freshwater crustaceans. With the growth of the crayfish industry, the associated food-safety risks should be seriously considered. Although Vibrio parahaemolyticus is commonly recognized as a halophilic foodborne pathogen associated with seafood, it has been found to be a major pathogen in crayfish-associated food poisoning cases. In this study, the V. parahaemolyticus contamination level in crayfish production-sale chain was investigated using crayfish and environmental samples collected from crayfish farms and markets. Serious V. parahaemolyticus contamination (detection rate of 66%) was found in the entire crayfish production-sale chain, while the V. parahaemolyticus contamination level of the market samples was extremely high (detection rate of 92%). The V. parahaemolyticus detection rate of crayfish surface was similar to that of whole crayfish, indicating that crayfish surface was important for V. parahaemolyticus contamination. The simulation experiments of crayfish for sale being contaminated by different V. parahaemolyticus sources were performed. All the contamination sources, containing V. parahaemolyticus-positive tank, water, and crayfish, were found to be efficient to contaminate crayfish. The crayfish tank displayed the most significant contaminating role, while the water seemed to inhibit the V. parahaemolyticus contamination. The contamination extent of the crayfish increased with the number of V. parahaemolyticus cells the tank carried and the contact time of the crayfish and the tank, but decreased with the time that the crayfish were maintained in the water. It was also confirmed that the crayfish surface was more susceptible to V. parahaemolyticus contamination than the crayfish intestine. Furthermore, the adsorption of V. parahaemolyticus onto the crayfish shell was analyzed. Over 90% of the V. parahaemolyticus cells were adsorbed onto the crayfish shell in 6 h, indicating a significant adsorption effect between V. parahaemolyticus and the crayfish shell. In conclusion, within a water-free sale style, the fresh crayfish for sale in aquatic products markets uses its shell to capture V. parahaemolyticus cells from the V. parahaemolyticus-abundant environments. The V. parahaemolyticus contamination in crayfish for sale exacerbates the crayfish-associated food-safety risk. This study sheds light on V. parahaemolyticus control and prevention in crayfish industry.

Although splenomegaly is a common finding in several diseases, massive splenomegaly is rare. Patients with massive splenomegaly often present with a complex clinical picture. This case report describes a 72-year-old female with a complex medical history. Fifteen years ago, she was diagnosed with primary myelofibrosis, which subsequently led to progressive abdominal enlargement and bloating over the past 5 years. Recently, she developed edema in her limbs, accompanied by dizziness, shortness of breath, and fatigue. A massive splenomegaly was discovered during her hospitalization. Additionally, the patient has a history of Crohn’s disease, gout, renal insufficiency, and hypertension. Laboratory results reveal severe anemia and thrombocytopenia. Abdominal CT scans confirm the enlarged spleen and show ascites. She was treated by a multidisciplinary team comprising several departments. Even after a period of comprehensive treatment, the symptoms of massive splenomegaly did not significantly improve. Thus, the patient underwent an open surgical excision of the giant spleen. The weight of the giant spleen was 5.0 kg. During the perioperative period, Enhanced Recovery After Surgery (ERAS) protocols were applied to facilitate recovery. Her recovery was uneventful, and she was able to resume her regular daily routine shortly after the procedure. This report presented a complex and rare case of massive splenomegaly, and underscored that a proper medical and nursing care is the key to better recovery.

This study intended to determine the molecular subtypes of liver hepatocellular carcinoma (LIHC) on the strength of anoikis-related genes (ARGs) and to assess their prognostic value and prospective relationship with immune cell infiltration and cancer-associated fibroblasts (CAFs). Univariate Cox regression analysis yielded 66 prognosis-related ARGs and classified LIHC into two distinct subtypes, with subtype A demonstrating overexpression of most prognosis-related ARGs and a significant survival disadvantage. Furthermore, a reliable prediction model was developed using ARGs to evaluate the risk of LIHC patients. This model served as an independent prognostic indicator and a quantitative tool for clinical prognostic prediction. Additionally, subtype-specific differences in immune cell infiltration were observed, and the risk score was potentially linked to immune-related characteristics. Moreover, the study identified a significant association between CAF score and LIHC prognosis, with a low CAF score indicating a favorable patient prognosis. In conclusion, this study reveals the molecular mechanisms underlying the development and progression of LIHC and identifies potential therapeutic targets for the disease.

Background: To investigate changes in the immunophenotypes of androgen receptor (AR), prostate-specific antigen (PSA), synaptophysin (Syn), chromogranin A (CgA), p53 and Ki-67 after neoadjuvant endocrine therapy (NET) for prostate cancer (PCa) and to analyze their clinical significance. Methods: Paired paraffin samples were collected from 40 PCa patients before and after NET, and immunohistochemistry were used to detect AR, PSA, Syn, CgA, p53 and Ki-67 expression. Based on The Cancer Genome Atlas (TCGA), Kaplan‒Meier survival curves were plotted for analysis of PSA and Ki-67 expression in relation to progression-free survival (PFS). Results: After NET, the mean scores for PSA and Ki-67 expression in PCa patients were lower than those before NET (P

Lung cancer (LC) is one of the most common cancer worldwide. Tumor-associated macrophages (TAMs) are important component of the tumor microenvironment (TME) and are closely related to the stages of tumor occurrence, development, and metastasis. Macrophages are plastic and can differentiate into different phenotypes and functions under the influence of different signaling pathways in TME. The classically activated (M1-like) and alternatively activated (M2-like) represent the two polarization states of macrophages. M1 macrophages exhibit anti-tumor functions, while M2 macrophages are considered to support tumor cell survival and metastasis. Macrophage polarization involves complex signaling pathways, and blocking or regulating these signaling pathways to enhance macrophages’ anti-tumor effects has become a research hotspot in recent years. At the same time, there have been new discoveries regarding the modulation of TAMs towards an anti-tumor phenotype by synthetic and natural drug components. Nanotechnology can better achieve combination therapy and targeted delivery of drugs, maximizing the efficacy of the drugs while minimizing side effects. Up to now, nanomedicines targeting the delivery of various active substances for reprogramming TAMs have made significant progress. In this review, we primarily provided a comprehensive overview of the signaling crosstalk between TAMs and various cells in the LC microenvironment. Additionally, the latest advancements in novel drugs and nano-based drug delivery systems (NDDSs) that target macrophages were also reviewed. Finally, we discussed the prospects of macrophages as therapeutic targets and the barriers to clinical translation.

Context: Ultrasound (US) is the most economical and widely used method for detecting lesions in parathyroid regions. Identifying typically parathyroid adenomas as hypoechoic nodules with clear margins. However, 10 % of lesions exhibit atypical features, such as the dual concentric sign, and the cognition of them still needs to be improved. Objective: To promote understanding of clinical and histopathological features for parathyroid lesions with the dual concentric echo sign and to investigate its pathogenesis and methods for distinguishing from cervical lymph nodes to improve US diagnostic accuracy. Methods: Retrospectively, patients were categorized into three groups: Group 1, with 36 patients showing parathyroid lesions with dual concentric echo signs; Group 2, with 40 patients displaying classic hypoechoic parathyroid lesions; and Group 3, comprising 36 patients with identified lymph nodes, which were all examined from January 2018 to December 2019. The clinical data on demographics, clinical symptoms, serum levels, histopathologic findings, and US image characteristics were thoroughly reviewed. Results: According to the clinical data, no significant differences in demographics or lesion sizes were observed in Group 1 and Group 2 (p > 0.05). No significant variances were noted in biochemical markers, including PTH, T-25OHD, and ALP. However, a notable difference was identified in adjusted serum calcium levels, which were significantly lower in Group 1 compared to Group 2 (p

Aberrant alternative splicing is well-known to be closely associated with tumorigenesis of various cancers. However, the intricate mechanisms underlying breast cancer metastasis driven by deregulated splicing events remain largely unexplored. Here, we unveiled that RBM7 is decreased in lymph node and distant organ metastases of breast cancer as compared to primary lesions and low expression of RBM7 is correlated with the reduced disease-free survival of breast cancer patients. Breast cancer cells with RBM7 depletion exhibited an increased potential for lung metastasis compared to scramble control cells. The absence of RBM7 stimulated breast cancer cell migration, invasion, and angiogenesis. Mechanistically, RBM7 controlled the splicing switch of MFGE8, favoring the production of the predominant isoform of MFGE8, MFGE8-L. This resulted in the attenuation of STAT1 phosphorylation and alterations in cell adhesion molecules. MFGE8-L exerted an inhibitory effect on the migratory and invasive capability of breast cancer cells, while the truncated isoform MFGE8-S, which lack the second F5/8 type C domain had the opposite effect. In addition, RBM7 negatively regulates the NF-κB cascade and an NF-κB inhibitor could obstruct the increase in HUVEC tube formation caused by RBM7 silencing. Clinically, we noticed a positive correlation between RBM7 expression and MFGE8 exon7 inclusion in breast cancer tissues, providing new mechanistic insights for molecular-targeted therapy in combating breast cancer.

The existing literature points towards the presence of robust mitochondrial mechanisms aimed at mitigating protein dyshomeostasis within the organelle. However, the precise molecular composition of these mechanisms remains unclear. Our data show that inorganic polyphosphate (polyP), a polymer well-conserved throughout evolution, is a component of these mechanisms. In mammals, mitochondria exhibit a significant abundance of polyP, and both our research and that of others have already highlighted its potent regulatory effect on bioenergetics. Given the intimate connection between energy metabolism and protein homeostasis, the involvement of polyP in proteostasis has also been demonstrated in several organisms. For example, polyP is a bacterial primordial chaperone, and its role in amyloidogenesis has already been established. Here, using mammalian models, our study reveals that the depletion of mitochondrial polyP leads to increased protein aggregation within the organelle, following stress exposure. Furthermore, mitochondrial polyP is able to bind to proteins, and these proteins differ under control and stress conditions. The depletion of mitochondrial polyP significantly affects the proteome under both control and stress conditions, while also exerting regulatory control over gene expression. Our findings suggest that mitochondrial polyP is a previously unrecognized, and potent component of mitochondrial proteostasis.

ABSTRACT Naphthoquine is a promising candidate for antimalarial combination therapy. Its combination with artemisinin has demonstrated excellent efficacy in clinical trials conducted across various malaria-endemic areas. A co-formulated combination of naphthoquine and azithromycin has also shown high clinical efficacy for malaria prophylaxis in Southeast Asia. Developing new combination therapies using naphthoquine will provide additional arsenal responses to the growing threat of artemisinin resistance. Furthermore, due to its long half-life, the possible interaction of naphthoquine with other drugs also needs attention. However, studies on its pharmacodynamic interactions with other drugs are still limited. In this study, the in vitro interactions of naphthoquine with ivermectin, atovaquone, curcumin, and ketotifen were evaluated in the asexual stage of Plasmodium falciparum 3D7. By using the combination index analysis and the SYBR Green I-based fluorescence assay, different interaction patterns of selected drugs with naphthoquine were revealed. Curcumin showed a slight but significant synergistic interaction with naphthoquine at lower effect levels, and no antagonism was observed across the full range of effect levels for all tested ratios. Atovaquone showed a potency decline when combined with naphthoquine. For ivermectin, a significant antagonism with naphthoquine was observed at a broad range of effect levels below 75% inhibition, although no significant interaction was observed at higher effect levels. Ketotifen interacted with naphthoquine similar to ivermectin, but significant antagonism was observed for only one tested ratio. These findings should be helpful to the development of new naphthoquine-based combination therapy and the clinically reasonable application of naphthoquine-containing therapies.IMPORTANCEPharmacodynamic interaction between antimalarials is not only crucial for the development of new antimalarial combination therapies but also important for the appropriate clinical use of antimalarials. The significant synergism between curcumin and naphthoquine observed in this study suggests the potential value for further development of new antimalarial combination therapy. The finding of a decline in atovaquone potency in the presence of naphthoquine alerts to a possible risk of treatment or prophylaxis failure for atovaquone–proguanil following naphthoquine-containing therapies. The observation of antagonism between naphthoquine and ivermectin raised a need for concern about the applicability of naphthoquine-containing therapy in malaria-endemic areas with ivermectin mass drug administration deployed. Considering the role of atovaquone–proguanil as a major alternative when first-line artemisinin-based combination therapy is ineffective and the wide implementation of ivermectin mass drug administration in malaria-endemic countries, the above findings will be important for the appropriate clinical application of antimalarials involving naphthoquine-containing therapies.

Cancer is a major disease with ever-increasing morbidity and mortality. The metabolites derived from traditional Chinese medicine (TCM) have played a significant role in combating cancers with curative efficacy and unique advantages. Ferroptosis, an iron-dependent programmed death characterized by the accumulation of lipid peroxide, stands out from the conventional forms of cell death, such as apoptosis, pyroptosis, necrosis, and autophagy. Recent evidence has demonstrated the potential of TCM metabolites targeting ferroptosis for cancer therapy. We collected and screened related articles published in or before June 2023 using PubMed, Google Scholar, and Web of Science. The searched keywords in scientific databases were ferroptosis, cancer, tumor, traditional Chinese medicine, botanical drugs, and phytomedicine. Only research related to ferroptosis, the metabolites from TCM, and cancer was considered. In this review, we introduce an overview of the current knowledge regarding the ferroptosis mechanisms and review the research advances on the metabolites of TCM inhibiting cancer by targeting ferroptosis.

Objectives: This paper aims to conduct research on the factors that impact the advancement of the tourism economy in order to adapt to the rapidly changing demands of the tourism market. Methods: A case study was performed using a gray correlation model to analyze the tourism industry in Henan Province. Findings: Among the first-level indicators, tourism economic support had the highest correlation with tourism economic development, followed by tourism physical base, tourism transportation influence, tourism human resources, and tourism information service. Then, relevant suggestions were given according to the analysis results. Novelty:The novelty of this article lies in utilizing the gray correlation model to examine the factors that influence the tourism economy and analyzing the gray system with incomplete information. Doi: 10.28991/HIJ-2024-05-01-03 Full Text: PDF

Abstract Asbestos is widely used in construction, manufacturing, and other common industrial fields. Human activities such as mining, processing, and transportation can release heavy metals from asbestos into the surrounding soil environment, posing a health hazard to the mining area's environment and its surrounding residents. The purpose of the present study was to determine the extent of ecological and human health damage caused by asbestos pollution, as well as the primary contributors to the contamination, by examining a large asbestos mine and the surrounding soil in China. The level of heavy metal pollution in soil and sources were analyzed using methods such as the geo-accumulation index (Igeo), potential ecological risk index (RI), and positive matrix factorization (PMF) model. A Monte Carlo simulation-based health risk model was employed to assess the health risks of heavy metals in the study area’s soil to human beings. The results showed that the concentrations of As, Pb, Cr, Cu, and Ni in the soil were 1.74, 0.13, 13.31, 0.33, and 33.37 times higher than the local soil background values, respectively. The Igeo assessment indicated significant accumulation effects for Ni, Cr, and As. The RI evaluation revealed extremely high comprehensive ecological risks (RI ≥ 444) in the vicinity of the waste residue heap and beneficiation area, with Ni exhibiting strong individual potential ecological risk (Eir ≥ 320). The soil health risk assessment demonstrated that As and Cr posed carcinogenic risks to adults, with mean carcinogenic indices (CR) of 1.56E − 05 and 4.14E − 06, respectively. As, Cr, and Cd posed carcinogenic risks to children, with mean CRs of 1.08E − 04, 1.61E − 05, and 2.68E − 06, respectively. Cr also posed certain non-carcinogenic risks to both adults and children. The PMF model identified asbestos contamination as the primary source of heavy metals in the soil surrounding the asbestos mining area, contributing to 79.0%. According to this study, it is recommended that management exercise oversight and regulation over the concentrations of Ni, Cr, Cd, and As in the soil adjacent to asbestos mines, establish a designated control zone to restrict population activities, and locate residential zones at a safe distance from the asbestos mine production zone.

Adopting the classical theory of hydrocodes, the constitutive relations of concretes are separated into an equation of state (EoS) which describes the volumetric behavior of concrete material and a strength model which depicts the shear properties of concrete. The experiments on the EoS of concrete is always challenging due to the technical difficulties and equipment limitations, especially for the specimen size effect on the EoS. Although some researchers investigate the shock properties of concretes by fly-plate impact tests, the specimens used in their tests are usually in one size. In this paper, the fly-plate impact tests on concrete specimens with different sizes are performed to investigate the size effect on the shock properties of concrete materials. The mechanical background of the size effect on the shock properties are revealed, which is related to the lateral rarefaction effect and the deviatoric stress produced in the specimen. According to the tests results, the modified EoS considering the size effect on the shock properties of concrete are proposed, which the bulk modulus of concrete is unpredicted by up to 20% if size effects are not accounted for.

The biomechanical behaviour of clear aligners can affect the clinical efficacy of tooth movement.

The new species, Harpiola isodon Kuo et al., 2006, was described from Taiwan, China. So far, no distribution of this species outside Taiwan has been reported.During two field investigations of small mammals in Guanyin Mountains Provincial Nature Reserve, Yuanyang, Yunnan, China, in April 2022 and May 2023, five individuals of Harpiola were collected in the mid-montane evergreen broad-leaved forest. Our morphological and molecular results reveal that these individuals from the Chinese mainland belong to Harpiola isodon, extending the occurrence of this species well beyond its known distributions in Taiwan, China and Vietnam.

To quantitatively and qualitatively analyse the content, reliability and quality of TikTok videos related to orthodontic fixed appliances.

Abstract Inverse halftoning is a technology that converts a binary image into a continuous tone image. Due to the wide application of inverse halftoning, many scholars have proposed several deep convolutional neural networks (DCNN) to optimize their performance. According to the observation, there is still room for improvement in content generation and detail recovery of the inverse halftone images generated by using the existing methods. Therefore, an inverse halftoning method based on supervised DCNN is proposed in this paper. The method consists of two parts: the multi‐level feature extraction model uses the down‐sampling to extract the features from the halftone image and remove the halftone noise dots on flat areas, which is implemented by four convolutional layers; the image reconstruction model uses up‐sampling to reconstruct image information, which is realized by four convolutional layers and two dense residual blocks. At the same time, in order to further recover the details, the down‐sampling feature maps and up‐sampling feature maps of the same size are concatenated by addition layers. Experimental results show that compared with other methods, the inverse halftone images obtained by the proposed network have better results in both subjective and objective evaluations.

Abstract Background Qualified malaria diagnosis competency has contributed to the great achievement of malaria elimination in China. After eliminating malaria, it is still critical to the prevention of re-establishment of malaria transmission in China. This study was aimed to assess the malaria detection competency at national and provincial levels in China at the beginning of malaria post-elimination phase. Methods In the present study, different competency assessment activities on the laboratory malaria diagnosis were carried out for national and provincial malaria diagnostic laboratories based on the WHO scoring schedules, including malaria microscopy or nucleic acid amplification tests (NAAT), at the beginning of malaria post-elimination phase (2021–2022) in China. Results A total of 60 slides for malaria microscopy and 10 specimen for NAAT were included into the WHO External Quality Assessments of malaria parasite qualitative detection and species identification, and the scoring rate was 96.6% (microscopy: 171/177) and 85.0% (NAAT: 17/20), respectively. Moreover, 124 samples were included into the national NAAT quality assessment, and an accuracy of 87.9% (109/124) was found without significance among reference laboratories and non-reference laboratories. Conclusions The findings suggest that there is still a need for sustained strengthening of malaria detection competency, particularly in the areas of parasite counting and detection of low-density parasitemia, to ensure prompt detection of the sources of infection and accurate identification of Plasmodium species, and contribute to case management and focus disposal, thereby effectively preventing the malaria re-establishment.

Abstract Background Glioblastoma (GBM) is a relatively prevalent primary tumor of the central nervous system in children, characterized by its high malignancy and mortality rates, along with the intricate challenges of achieving complete surgical resection. Recently, an increasing number of studies have focused on the crucial role of super-enhancers (SEs) in the occurrence and development of GBM. This study embarks on the task of evaluating the effectiveness of MZ1, an inhibitor of BRD4 meticulously designed to specifically target SEs, within the intricate framework of GBM. Methods The clinical data of GBM patients was sourced from the Chinese Glioma Genome Atlas (CGGA) and the Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and the gene expression data of tumor cell lines was derived from the Cancer Cell Line Encyclopedia (CCLE). The impact of MZ1 on GBM was assessed through CCK-8, colony formation assays, EdU incorporation analysis, flow cytometry, and xenograft mouse models. The underlying mechanism was investigated through RNA-seq and ChIP-seq analyses. Results In this investigation, we made a noteworthy observation that MZ1 exhibited a substantial reduction in the proliferation of GBM cells by effectively degrading BRD4. Additionally, MZ1 displayed a notable capability in inducing significant cell cycle arrest and apoptosis in GBM cells. These findings were in line with our in vitro outcomes. Notably, MZ1 administration resulted in a remarkable decrease in tumor size within the xenograft model with diminished toxicity. Furthermore, on a mechanistic level, the administration of MZ1 resulted in a significant suppression of pivotal genes closely associated with cell cycle regulation and epithelial-mesenchymal transition (EMT). Interestingly, our analysis of RNA-seq and ChIP-seq data unveiled the discovery of a novel prospective oncogene, SDC1, which assumed a pivotal role in the tumorigenesis and progression of GBM. Conclusion In summary, our findings revealed that MZ1 effectively disrupted the aberrant transcriptional regulation of oncogenes in GBM by degradation of BRD4. This positions MZ1 as a promising candidate in the realm of therapeutic options for GBM treatment.

To investigate the non-attendance of patients at orthodontic appointments and to determine related reasons.

The yellow seed trait is preferred by breeders for its potential to improve the seed quality and commercial value of Brassica napus. In the present study, we produced yellow seed mutants using a CRISPR/Cas9 system when the two BnPAP2 homologs were knocked out. Histochemical staining of the seed coat demonstrated that proanthocyanidin accumulation was significantly reduced in the pap2 double mutants and decreased specifically in the endothelial and palisade layer cells of the seed coat. Transcriptomic and metabolite profiling analysis suggested that disruption of the BnPAP2 genes could reduce the expression of structural and regulated genes in the phenylpropanoid and flavonoid biosynthetic pathways. The broad suppression of these genes might hinder proanthocyanidin accumulation during seed development, and thereby causing the yellow seed trait in B. napus. These results indicate that BnPAP2 might play a vital role in the regulatory network controlling proanthocyanidin accumulation.